A comprehensive evaluation of pathogenic mutations in primary cutaneous melanomas, including the identification of novel loss-of-function variants

Sci Rep. 2019 Nov 19;9(1):17050. doi: 10.1038/s41598-019-53636-x.


The most common histological subtypes of cutaneous melanoma include superficial spreading and nodular melanoma. However, the spectrum of somatic mutations developed in those lesions and all potential druggable targets have not yet been fully elucidated. We present the results of a sequence capture NGS analysis of 114 primary nodular and superficial spreading melanomas identifying driver mutations using biostatistical, immunohistochemical and/or functional approach. The spectrum and frequency of pathogenic or likely pathogenic variants were identified across 54 evaluated genes, including 59 novel mutations, and the newly identified TP53 loss-of-function mutations p.(L194P) and p.(R280K). Frequently mutated genes most commonly affected the MAPK pathway, followed by chromatin remodeling, and cell cycle regulation. Frequent aberrations were also detected in the genes coding for proteins involved in DNA repair and the regulation and modification of cellular tight junctions. Furthermore, relatively frequent mutations were described in KDR and MET, which represent potential clinically important targets. Those results suggest that with the development of new therapeutic possibilities, not only BRAF testing, but complex molecular testing of cutaneous melanoma may become an integral part of the decision process concerning the treatment of patients with melanoma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Biomarkers, Tumor / genetics
  • Cell Cycle / genetics
  • Chromatin Assembly and Disassembly / genetics
  • DNA Repair / genetics
  • Female
  • Gene Frequency / genetics
  • Genetic Predisposition to Disease / genetics*
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Loss of Function Mutation / genetics*
  • MAP Kinase Signaling System / genetics
  • Male
  • Melanoma / genetics*
  • Melanoma / pathology
  • Middle Aged
  • Proto-Oncogene Proteins B-raf / genetics
  • Skin Neoplasms / genetics*
  • Skin Neoplasms / pathology
  • Tight Junctions / genetics
  • Tumor Suppressor Protein p53 / genetics
  • Young Adult


  • Biomarkers, Tumor
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • Proto-Oncogene Proteins B-raf

Supplementary concepts

  • Melanoma, Cutaneous Malignant